Diabetic nephropathy (DN) is the most common cause of end stage renal disease. Accumulation of extracellular matrix (ECM) proteins in glomerulus is an early feature of DN. Therefore, a therapeutic intervention on the early pathological changes can slow down progression of diabetic kidney disease. However, there are no known therapies currently available that can prevent/treat the progressive lesion of glomerular histology in DN. Therefore, new therapeutic strategies are in need. Glomerular mesangial cell (MC) is the major source of mesangial matrix. It is known that overproduction of ECM proteins by MCs contributes to glomerular damages in early DN. We have previously shown that MC function is controlled by store-operated Ca2+ channel (SOC). We recently found that SOC in MCs suppressed ECM protein expression by inhibiting TGF-?1 pathway. Our findings, for the first of time, demonstrate that SOC-mediated Ca2+ signaling in MCs is an endogenous anti-fibrotic mechanism, and thereby dysfunction of the channel could lead to glomerular accumulation of ECM and fibrosis in diabetes. Inhibitor of Myogenic Family isoform a (I-mfa) is a cytosolic protein. We and others recently found that I-mfa was an endogenous inhibitor of SOC in native tissues. However, it is not known whether and how I-mfa contributes to development of DN. In pilot studies, we found that I-mfa expression level in MCs was significantly increased by high glucose (HG) and diabetes. Over expression of I-mfa increased fibronectin expression in cultured MCs. Importantly, deletion of I-mfa ameliorated albuminuria in diabetic mice. We further found that I-mfa protein expression in MCs was regulated by reactive oxygen species (ROS). These findings raise a possibility that I-mfa plays a role in DN and thus could be a potential therapeutic target for DN. We hypothesize that diabetes upregulates I-mfa protein expression in MCs through ROS/NF-?B pathway and the increased I-mfa stimulates TGF-?1/Smad3 pathway by inhibition of SOC, which results in ECM protein expression and glomerular mesangial expansion in diabetes. Three specific Aims will be addressed using both in vitro and in vivo settings. Aim I will determine if knockout/knockdown of I- mfa ameliorates kidney damage in mice with DN, Aim II will determine that I-mfa promotes ECM protein expression by inhibition of SOC, which results in activation of TGF-?1/Smad3 signaling in cultured MCs, and Aim III will delineate the mechanism by which diabetes/high glucose upregulates I-mfa expression in MCs: ROS/NF-?B pathway. The information obtained from this novel study will provide a new therapeutic strategy for patients with DN. In addition, we will establish novel in vivo drug/gene delivery systems which specifically target on glomerular MCs. Successful employment of the MC specific in vivo drug/gene delivery approaches will have clinical significance in treating MC-associated kidney diseases.